Tobacco addiction is a multi-factorial process, regulated by a number of pharmacological and physiological effects of tobacco smoke exposure. In addition to the well-known effects of tobacco derived nicotine on brain dopaminergic systems, other secondary reinforcers such as body mass regulation are also involved with the compulsive tobacco use. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism, leading to body mass stabilization or reduction. Current smoking cessation treatments fail in up to 70% of cases, for a variety of individualized reasons. One of the main reasons for recidivism, especially in females, is the potential for weight gain. The problem of weight gain during smoking cessation is well documented, and studies consistently recommend incorporation of body weight management strategies to patient management plans. The proposed studies will use a novel microneedle-enhanced transdermal codrug delivery approach to test a new pharmacological approach that we hypothesize will enhance smoking cessation efforts. Bupropion is considered a first-line treatment for smoking cessation, but the efficacy of this drug is relatively low. Hydroxybupropion (BUPOH) is an active metabolite of bupropion that may have significant drug delivery and therapeutic effect advantages over bupropion, including better chemical stability, reduced metabolic drug interaction potential, and an equal or higher potency at relevant drug targets. BUPOH itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs. The proposed studies will test whether chemical modification optimization of the BUPOH codrug will enhance its microneedle-assisted skin permeation making it suitable for transdermal delivery. Hydroxybupropion will be chemically combined with phentermine (PHEN), a widely used appetite suppressant. PHEN should have a more tolerable side-effect profile if delivered at a constant rate through transdermal delivery. We hypothesize that a transdermal codrug (mutual prodrug or hybrid drug) of PHEN linked to the smoking cessation drug, BUPOH, will make an effective microneedle-enhanced transdermal pharmacotherapy for smoking cessation and weight loss. The specific aims of this project are to: 1 - synthesize a series of PHEN and BUPOH codrugs designed to elucidate quantitative structure-permeability relationships (QSPR) for microneedle-enhanced transdermal flux and subsequent bioconversion rates. 2 - to measure the drugs' penetration and concurrent bioconversion in skin in vitro with microneedle use, and 3 - to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR database for transdermal codrugs with microneedle use, as well as help to identify the most promising codrug/microneedle system for eventual human use.